Ultraviolet radiation shapes dendritic cell leukaemia transformation in the skin

Gabriel K. Griffin (), Christopher A. G. Booth, Katsuhiro Togami, Sun Sook Chung, Daniel Ssozi, Julia A. Verga, Juliette M. Bouyssou, Yoke Seng Lee, Vignesh Shanmugam, Jason L. Hornick, Nicole R. LeBoeuf, Elizabeth A. Morgan, Bradley E. Bernstein, Volker Hovestadt (), Peter Galen () and Andrew A. Lane ()
Additional contact information
Gabriel K. Griffin: Dana-Farber Cancer Institute
Christopher A. G. Booth: Dana-Farber Cancer Institute
Katsuhiro Togami: Dana-Farber Cancer Institute
Sun Sook Chung: Dana-Farber Cancer Institute
Daniel Ssozi: Broad Institute of MIT and Harvard
Julia A. Verga: Broad Institute of MIT and Harvard
Juliette M. Bouyssou: Dana-Farber Cancer Institute
Yoke Seng Lee: Broad Institute of MIT and Harvard
Vignesh Shanmugam: Broad Institute of MIT and Harvard
Jason L. Hornick: Brigham and Women’s Hospital
Nicole R. LeBoeuf: Dana-Farber Cancer Institute and Brigham and Women’s Hospital
Elizabeth A. Morgan: Brigham and Women’s Hospital
Bradley E. Bernstein: Broad Institute of MIT and Harvard
Volker Hovestadt: Broad Institute of MIT and Harvard
Peter Galen: Broad Institute of MIT and Harvard
Andrew A. Lane: Broad Institute of MIT and Harvard

Nature, 2023, vol. 618, issue 7966, 834-841

Abstract: Abstract Tumours most often arise from progression of precursor clones within a single anatomical niche. In the bone marrow, clonal progenitors can undergo malignant transformation to acute leukaemia, or differentiate into immune cells that contribute to disease pathology in peripheral tissues1–4. Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are unclear. Here we investigate the development of blastic plasmacytoid dendritic cell neoplasm (BPDCN)—an unusual form of acute leukaemia that often presents with malignant cells isolated to the skin5. Using tumour phylogenomics and single-cell transcriptomics with genotyping, we find that BPDCN arises from clonal (premalignant) haematopoietic precursors in the bone marrow. We observe that BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet (UV) radiation. A reconstruction of tumour phylogenies reveals that UV damage can precede the acquisition of alterations associated with malignant transformation, implicating sun exposure of plasmacytoid dendritic cells or committed precursors during BPDCN pathogenesis. Functionally, we find that loss-of-function mutations in Tet2, the most common premalignant alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid, but not conventional, dendritic cells, suggesting a context-dependent tumour-suppressive role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites can shape the evolution of premalignant clones to disseminated cancer.

Date: 2023
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DOI: 10.1038/s41586-023-06156-8

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